1. Field of the Invention
The present invention concerns the use of 3'-deoxythymidin-2'-ene (3'-deoxy-2', 3 -didehydrothymidine) in treating patients infected with retroviruses.
2. Background Information
Acquired immunodeficiency syndrome (AIDS) is generally accepted to be a consequence of infection with the retrovirus variously termed human T-lymphotropic virus type III (HTLV-III), lymphadenopathy-associated virus (LAV), AIDS associated retrovirus (ARV), or human immunodeficiency virus (HIV). A number of compounds have demonstrated antiviral activity against this virus which include HPA-23 (D. Dormont, B. Spire, F. Barre-Sinoussi, L. Montagnier and J. C. Chermann, Ann. Inst. Pasteur/Virol., 75, 136E, (1985) and W. Rosenbaum, D. Dormont, B. Spire, E. Vilmer, M. Gentilini, C. Griscelli, L. Montagnier, F. Barre-Sinoussi and J. C. Chermann, Lancet i, 450, (1985)), interferons (D. D. Ho, K. L. Hartshorn, T. R. Rota, C. A. Andrews, J. C. Kaplan, R. T. Schoolkey and M. S. Hirsch, Lancet, i, 602, (1985)), , ribavirin (J. B. McCormick, J. P. Getchell, S. W. Mitchell and D. R. Hicks, Lancet, ii, 1367, (1984)), phosphonoformate (E. G. Sandstrom, J. C. Kaplan, R. E. Byington and M. S. Hirsch, Lancet, i 1480 (1984) and P. S. Sarin, Y. Taguchi, D. Sun, A. Thornton, R. C. Gallo and B. Oberg, Biochem. Pharmac., 34, 4075, (1985)), ansamycin (R. Anand, J. L. Moore, A. Srinivason, V. Kalyanaraman, D. Francis, P. Feorino and J. Curran, Abstracts of the International Conference on Acquired Immune Deficiency Syndrome (AIDS), April 14-17, Atlanta, GA, page 72, (1985)), suramin (H. Mitsuya, M. Popovic, R. Yarchoan, S. Matsushita, R. C. Gallo and S. Broder, Science, 226, 172, (1984); H. Mitsuya, S. Matsushita, M. E. Harper and S. Broder, Cancer Res., 45, 4583s, (1985) and E. DeClercq, Cancer Lett., 8, 9, (1979)), imuthiol (A. Pompidou, D. Zagury, R. C. Gallo, D. Sun. A. Thornton and P. S. Sarin, Lancet, ii, 1423, (1985)), penicillamine (P. Chandra and P. S. Sarin, Drug Res., 36, 184, (1986)), rifabutin (R. Anand, J. Moore, P. Feorino, J. Curran and A Srinivasan, Lancet, i, 97, (1986)), AL-721 (P. S. Sarin, R. C. Gallo, D. I. Scheer, F. Crews and A. S. Lippa, New Engl. J. Med., 313, 1289, (1985)), 3'-azido-3'deoxythymidine (W. Ostertag T. Cole, T. Crozier, G. Gaedicke, J. Kind, N. Kluge, J. C. Krieg. G. Roselser, G. Sheinheider, B. J. Weimann and S. K. Dube, Proceedings of the 4th International Symposium of the Princess Takamatsu Cancer Research Fund, Tokyo, 1973, Differentiation and Control of Malignancy of Tumor Cells, Eds. W. Nakahara, T. Ono, T. Sugimura and H. Sugano, page 485, University of Tokyo Press, Tokyo, (1974); W. Ostertag, G. Roseler, C. J. Kreig, T. Cole, T. Crozier, G. Gaedicke, G. Steinheider, N. Kluge and S. K. Dube, Proc. Natn. Acad. Sci. USA, 71, 4980, (1974); S. L. Dube, G. Gaedicke, N Kluge, B. J. Weimann, H. Melderis, G. Steinheider T. Crozier, H. Beckmann and W. Ostertag, Proceedings of the 4th International Symposium of the Princess Takamatsu Cancer Research Fund, Tokyo, 1973, Differentiation and Control of Malignancy of Tumor Cells, Eds. W. Nakahara. T. Ono, T. Sugimura and H. Sugano, page 99, University of Tokyo Press, Tokyo, (1974); S. K. Dube, I. B. Pragnell, N. Kluge, G. Gacdicke, G. Steinheider and W. Ostertag, Proc. Natn. Acad. Sci. USA, 72, 1863, (1975) and H. Mitsuya, K. J. Weinhold, P. A. Furman, M. H. St. Clair, S. Lehrman Nusinoff, R. C. Gallo, D. Bolognesi, D. W. Barry and S. Broder, Proc. Natn. Acad. Sci. USA, 82, 7096, (1985)), and more recently various 2', 3'-dideoxynucleosides (H. Mitsuya and S. Broder, Proc. Natn. Acad. Sci. USA, 83, 1911, (1986)), of which 2',3'-dideoxycytidine (ddCyd) is the most potent. A review of these and other compounds evaluated for their activities against HIV, as well as a discussion of the AIDS problem in general, has been presented (E. DeClercq, J. Med. Chem., 29, 1561, (1986)).
Applicants previously found 2', 3'-dideoxycytidin-2'-ene (2', 3'-dideoxy-2', 3'-didehydrocytidine; D4C) a derivative of 2', 3'-dideoxycytidine (ddCyd) to have antiviral activity against HIV (Lin et al, Biochem. Pharmacol, in press). This provided the stimulus to synthesis 3'-deoxythymidin-2'-ene (3'-deoxy-2', 3'-didehydrothymidine) even though Mitsuya and Broder, supra found 2', 3'-dideoxythymidine (3'-deoxythymidine) to be a very poor inhibitor of HTLV-III/LAV. Applicants' finding of potent antiviral activity with 3'-deoxythymidin-2'-ene was, therefore, unexpected based on their report.